title: PFKFB4 as a prognostic marker in non-muscle-invasive bladder cancer.
abstract: OBJECTIVE
  PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) is induced by hypoxia and is strongly associated with glycolysis. Previously, we reported that PFKFB4 expression level may serve as a predictor of progression in non-muscle-invasive bladder cancer (NMIBC). Here, the role of PFKFB4 in NMIBC and the relationship between PFKFB4 expression and biological behavior in bladder cancer was investigated.
  
  
  METHODS
  One hundred ninety-three primary NMIBC tissue specimens were analyzed by real-time PCR. Immunohistochemical staining was performed on 77 subsets of tumor samples. The results were compared with clinicopathologic parameters, and the Kaplan-Meier method and a multivariate Cox regression model were used to identify the prognostic value of PFKFB4 for recurrence and progression.
  
  
  RESULTS
  The mRNA expression levels of PFKFB4 were significantly higher in patients with high stage carcinoma and multiple tumors as compared to low stage and single tumors (P < 0.05 for each). Kaplan-Meier estimates revealed significant differences in time to recurrence and progression between low- and high-mRNA expression groups (log-rank test, P = 0.015 and 0.003, respectively). Multivariate Cox regression analysis revealed that the level of PFKFB4 expression is an independent predictor of bladder tumor progression (HR, 2.026; 95% CI, 1.177-3.488; P = 0.011). Immunohistochemical findings were generally concordant with mRNA expression levels.
  
  
  CONCLUSIONS
  PFKFB4 has an important role in the progression of NMIBC, and may serve as a useful prognostic indicator for bladder cancer progression.
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, South Korea.
authors.forename: Seok Joong
authors.initials: SJ
authors.lastname: Yun
authors.forename: Sung-Whan
authors.initials: SW
authors.lastname: Jo
authors.forename: Yun-Sok
authors.initials: YS
authors.lastname: Ha
authors.forename: Ok-Jun
authors.initials: OJ
authors.lastname: Lee
authors.forename: Won Tae
authors.initials: WT
authors.lastname: Kim
authors.forename: Yong-June
authors.initials: YJ
authors.lastname: Kim
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Lee
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D025481:Phosphofructokinase-2 / Q000032:analysis / Q000096:biosynthesis*; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C506672:PFKFB4 protein, human; D012333:RNA, Messenger; D025481:Phosphofructokinase-2